Human Leukocyte Antigens Flashcards
MHC represent _% of the genome
.1
What chromosome and arm is MHC on
Chromosome 6, short arm
The MHC contains a group of genes that encode what
Human leukocyte antigens HLA
Difference between MHC and HLA
MHC-collection of genes
HLA-human MHC
The T cell only recognizes antigens in the groove of an ____ molecule
HLA
Are differences in HLA responsible for organ and tissue rejection after transplantation
Yup
Some HLA genes are related to disease
Type 1 diabetes, MS, ankylosis spondylitis
HaplotypE
Collection of genes inherited as a whole group
Gene polymorphism
Availability in the gene pool of the population of many different allelic forms of a gene at a particular locus
Linkage disequilibrium
Alleles appearing together not he same haplotype more frequently. Than their single gene frequencies suggest;implies that meiosis recombination is non random
B27
Ankylosing spondylitis
MHC restriction
Antigen specific cytotoxic T cell responses are restricted ot kill only those target cells that bear the correct MHC molecule
What is in the human HLA/MHC
Three major classes, I, II, III, gene for 21 hydroxylase, TNFa, heat shock protein 70
Class I MHC
Furthest from centromere
HLA-A, B, C
Present peptide antigens to T cells
Why are MHC1 classical
Present peptide antigens to T cells
What do class 1 genes encode
A chains B chains
The class B chain joins the class a chain to create what
B2-microglobulin
Chat chromosome is the gene for B2 microglobulin on
15
Unlink the _ chain, the genes encoding the _ chains vary. The number of alleles can be considerable, it is called __ ___
B a gene polymorphism
How do we identify different HLA genes
HLA typing
What are non classical HLA class 1 genes
Ib less polymorphic , more restricted expression on specialized cell types and present a restricted type of peptide or none at all
What are the main genes of class Ib non classical HLA class I
HLA-A, F, G
*some have interactions with NK cells
MIC genes
Class Ic Genes lie between class I and III Code proteins with similar overall structure to class I , but do not bind peptide antigen to present to T cell
What are the two MHC class 1 related (MIC or class IC) genes
A and B
Are MIC polymorphic
Highly
MICA and MICB have over 70 alleles
Where are MIC genes expressed
Epithelial surface and participate in an interaction with lymphocytes that signals cellular stress
What are the three major subregions of class II HLA
DP, DQ, DR
What do DP, DQ, DR encode
Molecules that present antigen to T cells
What else is encoded in class II
HLA-DM, DO, TAP, PSMB
Two distinct polypeptide chains, _ and _ chains combine to form class II HLA DR, DQ, DP
A b
Class I and II are ____ bc they are made up of two different chains
Heterodimer
Why do all HLA-DR molecules have the same a chain
DR subregion contains only a single a chain gene (DRA
The number of DRB genes expressed in an individual depends on the ____
HaplotypE
DRA has _ allelic forms
No
The a chain is ___
Invariant
The DRB genes are highly ___
Variable
Like class I region, DRB is highly ____
Polymorphic
Since only the ___ genes are polymorphic, it is these that determine the particular HLA-DR type
DRB
In the DQ region, both DQA1 and DQAb are _____
Polymorphic
Int he DP region, DPA1 and DPB1 encode a and b chains. Are they polymorphic?
DP a chain low polymorphism DP b is highly polymorphic
DM—-DMA and DMB
Ab heterodiner
Rarely expressed on cell surface
Play role in loading peptide into the other “more conventional” class II HLA molecules
DO
HLA-DO
Role in regulating the antigen loading process
PSMB8 and 9 also in class II region
Code for proteosome subunit beta type 8 and 9
Proteins in the proteosome Cleave proteins into smaller peptides for binding to class I HLA
TAP1 TAP2
Encode one half of a peptide transporter responsible for transporting peptides of the required length into the class I synthesis compartment for loading
Class III region
Between classs I and II
Several genes coding for complement components
What are the three classes of HLA
I, II and III
What do class I and II encode
Proteins that physically present peptide antigens to T lymphocytes
What do class III HLA encode
Complement proteins
__ ___ in class I and II regions ensured that at a population level there are many different versions of clas I and II genes
Gene polymorphism
Each of us possess a discrete number of different class I and II genes
Ok
Two complementary chromosome strands, one maternal and one paternal are inherited each strand providing an MHC _____
Haplotype
What kind of expression do MHC have and what does this mean
Co-dominance
Both maternally and paternally derived allelic forms are expressed as cell surface proteins
HaplotypE encoding class II HLA are inherited in a similar fashion. Except what
HaplotypE int his region do not necessarily contain a full complement of DRB loci. However all HaplotypE contain the DRB1 locus which is the location of the best studies HLA-DR genes
What two things are special about MHC inheritance (although Mendelian)
Polymorphism
Linkage disequilibrium
Linkage disequilibrium
Certain alleles are found together on the Same haplotype with greater frequency than should occur if recombination during meiosis was random
Extended HaplotypE
Long segments of chromosome that incorporate genes from all three MHC classes and are passes on undisturbed from generation to generation
HLA typing
For transplantation
Amplify with pcr
What cells are class 1 molecules on
All cells except erythrocytes and trophoblasts
What are class II cells on
Macrophages Monocytes Dendritic cells B cells Not plasma cells
What are the antigen presenting cells
Macrophages and monocytes
Dendritic cells
B cells
Under the influence of cytokines during inflammation (interferons-a and y, TNF) a whole range of cells that typically only express MHC I may be induced to express ______ and _____ the number of MHCI…important for what
MHCII
Unregulated
Eradicate intracellular viral infections
Each of us expresses on the cell surface both maternally and paternally derived HLA molecules ; the genes are inherited in large chunks called ____
HaplotypE
Structure of class I molecule
HLAA, B, C are formed from polymorphic heavy chain glycoproteins that bind non covalently to the B chain, B2 microglobulin
Class II structure
HLA-DP, DQ, DR are formed from two glycoproteins , an a chain and a B chain
Describe binding of T cell to antigen and MHCI
T cell receptor encounters a deep grooved binding site, 2.5 no long, 1 no wide and 1 no deep, closed at either end and occupied by an antigenic peptide of around 9 aa residues in length . This groove is fashioned by 1 a helices which made up the sides, on top of a floor comprising eithe antiparalell b pleated sheets. The a helices and floor contain holes that can accomodate side chains poling out from the different aa in the bound peptide
What accounts for the difference between variations like A2 and A68
Polypeptide backbone very similar
Difference from nature of aa in position lining flow and sides of the groove
Sidechains of the pockets influence
Small differences in HLA can eve profound
Population level differences are ___
Polymorphism
Individual level differences are
Can express several different class I molecules by having multiple loci and co dominance increase Arnce of antigenic peptides
What is different about MHCII from MHCI
Peptide binding groove is larger and is not closed at either end allowing the peptide to protrude
Makes sense bc peptides are almost double the length on MHCII than MHCI
The source of a peptide dictates what
Wherther is it bound to MHCI or II
Antigens are degraded inside cells and the ___ are bound to HLA
Peptides
What peptides are bound to MHCI
Peptides derived from proteins synthesized endogenously within the cell presenting the antigen
MHCI can display __ proteins. Why
Viral
During a viral infection, viral proteins are synthesized endogenously using the host cells machinery.
What peptides are bound to MHCII
Peptides derived from outside cell (exogenous antigens) are taken into cell, processed using proteolytic enzymes and presented
What use the endogenous pathway what uses the exogenous pathway
Endogenous I
Exogenous II
What types of peptides are on MHCII
Plasma proteins
This changes during infection
MHC restriction
Only T cells bearing a surface glycoproteins molecule that binds to a fixed non varying point on the clas II B chain, are able to interact with clas II presented peptides
What is the function of CD4 and CD8 accessory molecules
Stabilize interaction fo T cell receptor and hla molecule-peptide compels
From a class I MHC, the eluded peptides are typically _ aa longand composed of endogenous proteins
9
What kind of forces fit the aa into MHCI
Non covalent
H bonding and van dear walls and electrostatic forces
Each sidechain slides into the pockets, labeled 1-9
What are the major anchoring pockets
P2 P9
Therefore, the P2 and P9 position pockets are ___
Constant
Motif
The characteristic sequence of a peptide for a particular HLA molecule
Why may the middle region of the peptide bulge out of MHCI
May be forced to bend to fit in class I This bulging part is what T cell interacts with
The binding of peptide to a class I molecules is __ than to a class II molecule
Tighther
Since binding to class I is stronger it can be considered ___
Irreversible
Half life of MHC complex on cell
30 hours
What is the dissociation constant
Ration between the rate at which molecules associate and dissociate
Antigen and antibody associate ___ and dissociate —-
Faster slower
What is the kinetics of the molecule peptide interaction
10^-5 to 10^-6, slow association and very slow dissociation
What is the major difference in MHCII
Longer peptide
Groove is open at each end so peptide hangs out at each side(no bulge)
Looser fit for peptides
With no infection what is in MHCII. What about with infection
Plasma membrane associated proteins and others…
Bacteria
Describe exogenous pathway
Proteins internalized into the endosomal and lysosomal compartments, where clas II HLA molecules are loaded….if bacterium internazlied at same time, peptide fragments fromt his pathogen willl also be presented
The peptides found in class II HLA are how many aa long
13-18
The pockets for interaction between peptide and class II groove are -
P1-P9 also
What are the major,
P1, P4, P6, P9
Different HLA molecules have different have different structural features in these pockets bc of ____
Polymorphism
Peptide binding motif
HLAII molecules can be characterized as this
Class II peptides display ____, in other words the same peptide may bind to several different types of class II molecules
Promiscuity
Class I genetic organization
Polymorphic a chain genes in MHC (on chromosome 6 in humans)
Monomorphic B chain gene (on chromosome in 15 in humans )
Class II molecules genetic organization
Polymorphic a and B chain genes in MHC (on chromosome 6 in humans)
Class I molecule molecular structure
Non-covalently associated ab dimer
Class II molecular structure
Non-covalently associated ab dimer
Class I binding groove
Two a helices flanking a floor of B pleated sheets
Class II binding groove
Two a helices flanking a floor of B pleated sheets
Peptide size class I
8-10 aa
Class II peptide size
10-34usuually 15
Class I peptide source
Endogenous proteins (including virus infected cells
Class II molecules peptide source
Exogenous and endogenous proteins derived from endosomal compartments situated near plasma membrane
Class I cellular site of peptide binding
Early-during assembly of class I molecule
Peptide required for correct folding of dimer
Class II cellular site of peptide binding
Late:in a specialized endosome
Invariant chain(but not peptide) required for folding of dimer
Class I affinity of peptide
High
Class II affinity for peptide
Moderate
What is polymorphism
Numerous different alleles can occur at a single locus
Since MHC co-dominant, do heterozygous or homozygous have the advantage
Heterozygous can make more combinations
Can a groove of MHC accomodate all peptides
No, but a range
Polymorphism has 2 important consequences for an individual what are they.
Unrelated individuals have a diverse susceptibility to disease and also promptly reject organ transplants between each other
The extended HaplotypE HLA-A *0101, HLA-B *0801, HLA-DRB! *0301 and complement C4AQO
Present on a dingle chromosome together and occur in patients with a range of diseases that under the umbrella term “inflammatory or autoimmune “
Vascultis or diabetes
Common in Caucasian’s enhanced survivial from a viral or bacterial epidemic afflicting Northern Europe millenia ago
*aggressive hyperresponsiveness may leave individuals prone to developing inappropriate immune responses giving a greater tendency towards chronic inflammatory conditions and responses to self antigens
Where do variable regions responsible for polymorphism generally lie
Along a helices that form margin of groove and B pleated sheets where the pockets are
How does TCR interact with the complex
TCR straddles the peptide binding groove of HLA at an angle of 45 degrees
Why tcr bind at 45 degrees
Two hypervariable regions (CDR1 and CDR2 of the a chain) bind one a helix whilst two other hypervariable regions (CDR1 and CDR2 of the b chain) bind the other a helix of the HLA molecule
What regions of the TCR are the only parts to interact with the peptide
CDR3 regions of a and b chains
Can TCR bind to different peptides yea if has center of the groove contains the same of similar aa
One tcr can recodgnize more than one peptide
Nomenclature for class 1 Example: HLA-A*0101
A is thee allel
Asterisk then two digit number defining HLA type
Then two digitr for the variants of that type
Nomenclature class II example HLA-DRB1*0101
Letters defining locus followed by A or B for A or B chain
Number defining locus if more than 1 exists
First two letters for types
Second two letters for variants
